1. Field of the Invention
This invention relates generally to cancer therapy, and more particularly to methods for preventing or minimizing neurotoxicity associated with cancer therapy using DPD inhibitors in combination with 5-FU and/or 5-FU prodrugs.
2. Description of the Related Art
5-Fluorouracil (5-FU) has been clinically used to treat solid tumors in cancer patients for over three decades (Ansfield et al., Cancer 39: 34-40, 1977; Grem et al., Cancer Treat Rep 71: 1249-1264, 1987; Chabner et al., Cancer, Principles and Practice of Oncology, 2nd Ed, pp 287-328 Philadelphia, Pa.: J B Lippincott Co, 1985). 5-FU must be activated by metabolic conversion to fraudulent uridine nucleotides (e.g., FUMP, FUDP, FUTP) and deoxyuridine nucleotides (e.g., FdUMP, FdUDP, FdUTP) that interfere with DNA synthesis and RNA functions (reviewed in Meyers, Pharmacol Rev, 33: 1-15, 1981; Dasher et al., Pharmac Ther 48: 189-222, 1990). Because 5-FU differs from uracil, its natural counterpart, by only a fluorine substitution in the 5-position, it is readily activated in cancer patients. Unfortunately, its structural similarity to uracil also accounts for its rapid and extensive conversion to products that have no antitumor activity. This metabolic process is referred to as catabolism. 5-FU is rapidly catabolized by the enzyme dihydropyrimidine dehydrogenase (DPD: EC 1312, uracil reductase) (Meyers, Pharmacol Rev, 33: 1-15, 1981; Dasher et al., Pharmac Ther 48: 189-222, 1990). Therefore, the antitumor efficacy of 5-FU for treating cancer relies on the delicate balance between metabolic conversion to antitumor nucleotides (activation) and metabolic conversion to useless metabolites (catabolism).
Furthermore, several clinical issues arise due to the metabolic catabolism of 5-FU. Firstly, because the levels of DPD vary among individuals (Fleming et al., Cancer Res 52: 2899-2902, 1992; Grem et al., Cancer Chemother Pharmacol 40: 117-125, 1997) and within individuals during the course of a day (Grem et al., Cancer Chemother Pharmacol 40: 117-125, 1997; Harris et al., Cancer Res 50: 197-201, 1990; Petit et al., Cancer Res 48: 1676-1679, 1988), the systemic levels of 5-FU or 5-FU generated from a prodrug produced from a given dose vary greatly, and therefore, render efficacy and toxicity highly unpredictable. At the extreme, patients genetically deficient in DPD experience severe and sometimes fatal toxicity when treated with ‘standard’ therapeutic doses of 5-FU (reviewed in Morrison et al., Oncol Nurs Forum 24: 83-88, 1997). Secondly, variable levels of gastro-intestinal DPD (Ho et al., Anticancer Res 6: 781-784, 1986; Naguib et al., Cancer Res 45: 5405-5412, 1985; Spector et al., Biochem Pharmacol 46: 2243-2248, 1993) create highly variable absorption of orally dosed 5-FU (Christophidis et al., Clin Pharmacokinetics 3: 330-336, 1978; Cohen et al., Cancer Chemother Rep 58: 723-731, 1974; Finch et al., Br J Clin Pharmacol 7: 613-617, 1979) that can result in unpredictable plasma levels of drug and produces undesirable toxicity or inadequate efficacy. Thirdly, tumors containing high levels of DPD are less likely to respond to 5-FU-treatment (Etienne et al., J Clin Oncol 13: 1663-1670, 1995; Fischel et al., Clin Cancer Res 1: 991-996, 1995).
Finally, the breakdown products of 5-FU, such as F-Bal, may produce neurotoxicity (Okeda et al., Acta Neuropathol 81: 66-73, 1990; Koenig et al. Arch Neurol 23: 155-160, 1970; Davis S T, et al. Biochem Pharmacol 1994; 48:233-6; reviewed in Saif M W, et al. Anticancer Drugs 2001; 12:525-31.), cardiotoxicity (et al., Lancet 337: 560, 1991; Lemaire et al., Br J Cancer 66: 119-127, 1992), palmer-plantarerythrodysaesthesia (hand-foot syndrome) (Hohneker, Oncology 12: 52-56, 1998), and GI toxicity (Spector et al., Cancer Res 55: 1239-1241, 1995) and appear to interfere with the antitumor activity (Spector et al., Cancer Res 55: 1239-1241, 1995; Cao, et al., Pharmacol 59: 953-960, 2000).
DPD is a ubiquitous enzyme that is the first and the rate-limiting step in the degradation (catabolism) of 5-FU. Studies have shown that inhibition of DPD greatly increases the half-life of 5-FU in plasma. Several DPD inhibitors have been studied, including those that irreversibly inactivate DPD as well as those that reversibly inhibit DPD. For example, eniluracil (5-ethynyluracil, 776C85) is a potent irreversible inactivator of DPD. Because DPD and the sequential enzymes in the catabolic pathway eventually convert 5-FU to α-fluoro-β-alanine (F-Bal) (reviewed in Spector et al., Drugs of The Future 1994; 19:565-71; Paff et al., Invest New Drugs 2000; 18:365-71), eniluracil converts the route of 5-FU elimination from catabolism to renal excretion, and, thereby increases the 5-FU elimination half-life from 10-20 min to 4.5-6.5 hr (Adjei et al., J Clin Oncol 2002; 20:1683-91; Ochoa et al., Ann Oncol 2000; 11:1313-22; Baker, Invest New Drugs 2000; 18:373-81; Baker et al., J Clin Oncol 1996; 14:3085-96; Guo et al., Cancer Chemother Pharmacol 2003; 52:79-85; Schilsky et al., J Clin Oncol 1998; 16:1450-7).
By preventing 5-FU breakdown in the gastrointestinal tract, eniluracil also enables 5-FU to be administered orally (Baker et al., J Clin Oncol 1996; 14:3085-96). In addition, eniluracil prevents the formation of 5-FU catabolites, such as F-Bal, that appear to be responsible for 5-FU-associated neurotoxicity (Davis et al., Biochem Pharmacol 1994; 48:233-6 reviewed in Saif M W, et al. Anticancer Drugs 2001; 12:525-31), and for hand-foot toxicity syndrome (Schilsky et al., J Clin Oncol 2002; 20:1519-26). In addition, 5-FU catabolites, such as F-Bal, appear to decrease the antitumor activity of 5-FU (Cao et al., Biochem Pharmacol 2000; 59:953-60; Spector T, et al. Cancer Res 1995; 55:1239-41 Spector et al., Drugs of The Future 1994; 19:565-71; Paff et al., Invest New Drugs 2000; 18:365-71).
Furthermore, because DPD is present in patients at different levels, the highly variable and nonlinear pharmacokinetics of 5-FU become highly predictable and linear when DPD is inactivated by eniluracil (reviewed in Baker, Invest New Drugs 2000; 18:373-81). Indeed, eniluracil significantly improved the antitumor efficacy of 5-FU and increased the therapeutic index in laboratory animals bearing tumors (Baccanari et al., Proc Natl Acad Sci USA 1993; 90:11064-812; Cao et al., Cancer Res 1994; 54:1507-10).
Eniluracil has been tested in Phase I clinical trials in cancer patients (reviewed in Levin et al., Invest New Drugs 18:383-90, 2000; Baker et al., J Clin Oncol 18: 915-926 2000; Schilsky et al., J Clin Oncol 4:1450-7, 1998). In these studies, eniluracil very potently eliminated DPD activity without causing toxicity. For example, a dose of 0.74 mg/m2 (about 1 mg total) eliminated greater than 90% of DPD in peripheral blood cells for prolonged periods. The elimination half-life of 5-FU was increased from about 10 minutes to 3.5 hours by one dose of eniluracil. A dose of 3.7 mg/m2 eniluracil increased the half-life of 5-FU to 4.5-6.5 hours. Higher doses added no apparent benefit.
Subsequently, two multicenter Phase III studies were conducted in patients with colorectal cancer using a combination pill containing eniluracil in ten-fold excess to 5-FU. Patients received 10 mg per square meter body surface area (mg/m2) eniluracil and 1 mg/m2 5-FU every 12 hr for 28 days. After one week off drug, the cycle was repeated. Although the results from the North American trial, where compliance was not a problem, showed encouraging antitumor activity, high tolerability, and minimal hand-foot syndrome, the regimen tended to produce less antitumor benefit than the standard regimen of 5-FU/leucovorin without eniluracil (Schilsky et al., J Clin Oncol 2002; 20:1519-26). An explanation of these results was not apparent at the time.
WO 2006/060697 describes the important finding that the antitumor activity of 5-FU is significantly diminished when excess eniluracil is present at the time 5-FU is administered to a subject. Therefore, to maximize the antitumor activity of 5-FU, low doses of eniluracil are proposed to be administered well before 5-FU such that at the time of 5-FU administration, 5-FU should be present in substantial excess to eniluracil. Otherwise, the antitumor efficacy of the 5-FU may be compromised. These results provide an explanation for the less than expected antitumor activity in the Phase III trials where the eniluracil ratio to 5-FU was 10:1 when 5-FU was administered.
Therefore, a clinical trial was initiated wherein cancer patients were administered a 5 mg dose of eniluracil followed by 5-FU at a 30-160 mg dose 12-24 hours later. Unexpectedly, the majority of the 41 patients undergoing this treatment experienced some form of mild to severe neurotoxicity, with the main neurological symptoms being ataxia (an unsteady gait), neuropathy, confusion, dizziness, and slurred speech.
Clearly, there remains an important and unmet need in the art for identifying optimal dosing and administration schedules for DPD inhibitors used in combination with 5-FU and 5-FU prodrugs in order to prevent or minimize neurotoxicity, to maximize the antitumor efficacy and therapeutic index of 5-FU and 5-FU prodrugs, to improve the predictability of dosing and to enable 5-FU and 5-FU prodrugs to be effectively dosed by oral administration. The present invention fulfills these needs and offers other related advantages.